CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
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`APPLICATION NUMBER:
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`213051Orig1s000
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`
`
`Rybelsus
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`
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`Trade Name:
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`Generic or Proper
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`Name:
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`Sponsor:
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`Approval Date:
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`Indication:
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`Semaglutide
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`Novo Nordisk Inc.
`September 20, 2019
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`
`
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`tablets as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus.
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`213051Orig1s000
`
`
`CONTENTS
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`Reviews / Information Included in this NDA Review.
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`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Clinical Review(s)
`Product Quality Review(s)
`Non-Clinical Review(s)
`Statistical Review(s)
`Clinical Microbiology / Virology Review(s)
`Clinical Pharmacology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
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`X
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`X
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`X
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`X
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`X
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`X
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`X
`X
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`X
`X
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`X
`X
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`

`

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`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`
`213051Orig1s000
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`
`
`APPROVAL LETTER
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`
`

`

`
`
`
`
` NDA 213051
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`
`
`
`
` NDA APPROVAL
`
`
`
`Novo Nordisk Inc.
`
`
`Attention: Stephanie DeChiaro
`
`
`
`Senior Director, Regulatory Affairs
`
`
`800 Scudders Mill Rd.
`
`
`P.O. Box 846
`
`
`Plainsboro, NJ 08536
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`
`
`
`
`Dear Ms. DeChiaro:
`
`
`
`Please refer to your new drug application (NDA) dated and received March 20, 2019,
`
`
`and your amendments, submitted under section 505(b) of the Federal Food, Drug, and
`
`
`
`
`Cosmetic Act (FDCA) for Rybelsus (semaglutide) tablets.
`
`
`
`
`
`
`This new drug application provides for the use of Rybelsus (semaglutide) tablets as an
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`adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`
`mellitus.
`
`
`APPROVAL & LABELING
`
`We have completed our review of this application, as amended. It is approved, effective
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`
`
`on the date of this letter, for use as recommended in the enclosed agreed-upon
`
`labeling.
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`
`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
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`
`
`
`
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of
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`
`Highlights of Prescribing Information. This waiver applies to all future supplements
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`containing revised labeling unless we notify you otherwise.
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`
`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the
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`
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`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
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`
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`the FDA automated drug registration and listing system (eLIST), as described at
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`
`
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`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
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`
`
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`Prescribing Information and Medication Guide) as well as annual reportable changes
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`
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`not included in the enclosed labeling. Information on submitting SPL files using eLIST
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`
`
`
`
` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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`
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`
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`Reference ID: 4494169Reference ID: 4497378
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`

`

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` NDA 213051
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`Page 2
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` may be found in the guidance for industry SPL Standard for Content of Labeling
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` Technical Qs and As.2
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`
`The SPL will be accessible via publicly available labeling repositories.
`
`
`CARTON AND CONTAINER LABELING
`
`
`
`Submit final printed carton and container labeling that are identical to the enclosed
`
`
`
`
`carton and container labeling as soon as they are available, but no more than 30 days
`after they are printed. Please submit these labeling electronically according to the
` guidance for industry Providing Regulatory Submissions in Electronic Format — Certain
`
`
`
`
`
`
` Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
`Specifications. For administrative purposes, designate this submission “Final Printed
`
` Carton and Container Labeling for approved NDA 213051.” Approval of this
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`
`
`
` submission by FDA is not required before the labeling is used.
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`
`
`
` REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`
`
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`new active ingredients (which includes new salts and new fixed combinations), new
`
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`indications, new dosage forms, new dosing regimens, or new routes of administration
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`
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`are required to contain an assessment of the safety and effectiveness of the product for
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`the claimed indication in pediatric patients unless this requirement is waived, deferred,
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`or inapplicable.
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`We are waiving the pediatric study requirement for ages 0 through 9 years (inclusive)
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`
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`because necessary studies are impossible or highly impracticable. This is because
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`there are too few children in this age range with type 2 diabetes mellitus to study.
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`
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`We are deferring submission of your pediatric study for ages 10 to 17 years (inclusive)
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`for this application because this product is ready for approval for use in adults and the
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`
`pediatric study has not been completed.
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`
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`Your deferred pediatric study required under section 505B(a) of the FDCA is a required
`
`
`postmarketing study. The status of this postmarketing study must be reported annually
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`
`
`according to 21 CFR 314.81 and section 505B(a)(3)(C) of the FDCA. This required
`
`
`study is listed below.
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`
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`3692-1 Conduct a 52-week, randomized, double-blind, placebo-controlled parallel
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`
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`group study of the safety and efficacy of Rybelsus (semaglutide) tablets
`
`
`for the treatment of type 2 diabetes mellitus in pediatric patients ages 10
`
`
`
`
`
`
`
` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`
`
`Reference ID: 4494169Reference ID: 4497378
`
`

`

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`
` NDA 213051
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`Page 3
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` to 17 years (inclusive). Background therapy will consist of either
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`
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` metformin, insulin, or metformin plus insulin.
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`
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`Draft Protocol Submission: November 2019
`
`
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`Final Protocol Submission: May 2020
`
`
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`December 2026
`
`Study Completion:
`
`
`
`Final Report Submission: June 2027
`
`
`
`
`
`
`Submit the protocol to your IND 114464, with a cross-reference letter to this NDA.
`
`
`
`Reports of this required pediatric postmarketing study must be submitted as a new drug
`
`application (NDA) or as a supplement to your approved NDA with the proposed labeling
`
`
`changes you believe are warranted based on the data derived from these studies.
`
`When submitting the reports, please clearly mark your submission "SUBMISSION OF
`
`
`
`
`REQUIRED PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of
`
`
`the cover letter of the submission.
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`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
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`
`
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`biological product applications to conduct postmarketing studies and clinical trials for
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`
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`certain purposes, if FDA makes certain findings required by the statute.
`
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`We have determined that an analysis of spontaneous postmarketing adverse events
`
`
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`reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal
`
`
`of a serious risk of medullary thyroid carcinoma associated with Rybelsus
`
`
`(semaglutide), and to assess the nonclinical signal of a risk of concentration of
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`
`
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`semaglutide and salcaprozate sodium in breast milk.
`
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under
`
`section 505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
`
`
`
`Therefore, based on appropriate scientific data, FDA has determined that you are
`
`
`
`required to conduct the following:
`
`
`
`
`3692-2 Conduct a medullary thyroid carcinoma registry-based case series of at
`
`
`
`least 15 years duration to systematically monitor the annual incidence of
`
`medullary thyroid carcinoma in the United States and to identify any
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`increase related to the introduction of Rybelsus (semaglutide) tablets into
`
`
`
`
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`the marketplace. This study will also establish a registry of incident cases
`
`
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 4494169Reference ID: 4497378
`
`

`

`NDA 213051
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`
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`Page 4
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`of medullary thyroid carcinoma and characterize their medical histories
`
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`related to diabetes and use of Rybelsus (semaglutide) tablets.
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`
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`The timetable you submitted on September 13, 2019, states that you will conduct this
`
`study according to the following schedule:
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`
`
`Draft Protocol Submission:
`
`
`Final Protocol Submission:
`
`Interim Report Submissions:
`
`
`May 2020
`
`November 2020
`
`March 2021
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`March 2022
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`March 2023
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`March 2024
`
`March 2025
`
`March 2026
`
`March 2027
`
`March 2028
`
`March 2029
`
`March 2030
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`March 2031
`
`March 2032
`
`March 2033
`
`March 2034
`
`March 2035
`
`February 2036
`
`February 2037
`
`
`Study Completion:
`
`
`Final Report Submission:
`
`
`
`
`
`3692-3 Conduct a milk-only lactation study in lactating women who have received
`
`
`
`Rybelsus (semaglutide) tablets therapeutically to assess concentrations of
`
`
`
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`semaglutide and salcaprozate sodium (SNAC) in breast milk using a
`
`validated assay.
`
`
`
`The timetable you submitted on September 13, 2019, states that you will conduct this
`
`study according to the following schedule:
`
`
`
`Final Protocol Submission: December 2020
`
`
`
`December 2022
`
`Study Completion:
`
`
`Final Report Submission: December 2023
`
`
`
`
`
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`Submit clinical protocols to your IND 114464 with a cross-reference letter to this NDA.
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`
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`Submit nonclinical and chemistry, manufacturing, and controls protocols and all final
`
`
`
`
`report(s) to your NDA. Prominently identify the submission with the following wording in
`
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`bold capital letters at the top of the first page of the submission, as appropriate:
`
`
`
`
`Required Postmarketing Protocol Under 505(o), Required Postmarketing Final
`
`Report Under 505(o), Required Postmarketing Correspondence Under 505(o).
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`
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`
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 4494169Reference ID: 4497378
`
`

`

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` NDA 213051
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`Page 5
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` Submission of the protocols for required postmarketing observational studies to your
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`
`
` IND is for purposes of administrative tracking only. These studies do not constitute
`clinical investigations pursuant to 21 CFR 312.3(b) and therefore are not subject to the
`IND requirements under 21 CFR part 312 or FDA’s regulations under 21 CFR parts 50
`
`
`
`
`
`(Protection of Human Subjects) and 56 (Institutional Review Boards).
`
`
`
`
` Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of
` any study or clinical trial required under this section. This section also requires you to
`
`periodically report to FDA on the status of any study or clinical trial otherwise
`undertaken to investigate a safety issue. Section 506B of the FDCA, as well as 21 CFR
`
`
`
`314.81(b)(2)(vii) requires you to report annually on the status of any postmarketing
`
`
`
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`commitments or required studies or clinical trials.
`
`
`
` FDA will consider the submission of your annual report under section 506B and
`
`
`
`
` 21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
` 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and
`
`
`
`
`
` 21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report
` must also include a report on the status of any study or clinical trial otherwise
`
`
`
`
` undertaken to investigate a safety issue. Failure to submit an annual report for studies
`
`
`
` or clinical trials required under 505(o) on the date required will be considered a violation
`
` of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
`
`
`
` POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
`
`
`We remind you of your postmarketing commitments:
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`
`
`
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`3692-4 Develop a sensitive assay to assess the neutralizing activity of anti­
`
`
`semaglutide antibodies and its cross-neutralizing effect on native GLP-1.
`
`
`
`The timetable you submitted on September 13, 2019, states that you will conduct this
`
`study according to the following schedule:
`
`
`
`October 2020
`
`Study Completion:
`
`
`Final Report Submission: December 2020
`
`
`
`
`
`
`
`3692-5 Assess the incidence of neutralizing antibodies to semaglutide and GLP-1
`
`
`in subjects treated with Rybelsus (semaglutide) tablets. The samples can
`
`
`
`
`
`be derived from pre-existing clinical studies, but a plan to select the
`
`
`
`
`samples should be agreed upon with the Agency.
`
`
`
`The timetable you submitted on September 13, 2019, states that you will conduct this
`
`
`study according to the following schedule:
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 4494169Reference ID: 4497378
`
`

`

`
`
` NDA 213051
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`Page 6
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`
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` May 2021
`
` Study Completion:
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`
`
`
` Final Report Submission: June 2021
`
`
`
`
`
`
`
`
`
`
` PROMOTIONAL MATERIALS
`
` You may request advisory comments on proposed introductory advertising and
`
`
`
`
`
` promotional labeling. To do so, submit, in triplicate, a cover letter requesting advisory
` comments, the proposed materials in draft or mock-up form with annotated references,
`
` and the Prescribing Information, Medication Guide, and Patient Package Insert (as
`
`
` applicable) to:
`
`
`
`OPDP Regulatory Project Manager
`
`
`Food and Drug Administration
`
`
`
`Center for Drug Evaluation and Research
`
`
`Office of Prescription Drug Promotion
`
`
`5901-B Ammendale Road
`
`
`Beltsville, MD 20705-1266
`
`
`
`
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD
`
`
`
`
`format. For more information about submitting promotional materials in eCTD format,
`
`
`
`see the draft guidance for industry Providing Regulatory Submissions in Electronic and
`Non-Electronic Format—Promotional Labeling and Advertising Materials for Human
`
`Prescription Drugs.3
`
`
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials,
`
`
`
`and the Prescribing Information, at the time of initial dissemination or publication,
`
`
`
`accompanied by a Form FDA 2253. Form FDA 2253 is available at FDA.gov.4
`
`
`
`Information and Instructions for completing the form can be found at FDA.gov.5 For
`
`
`more information about submission of promotional materials to the Office of Prescription
`
`Drug Promotion (OPDP), see FDA.gov.6
`
`
`REPORTING REQUIREMENTS
`
`
` We remind you that you must comply with reporting requirements for an approved NDA
`
` (21 CFR 314.80 and 314.81).
`
`
`
`
`
`
`
`
`
`
`
` 3 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent
` version of a guidance, check the FDA guidance web page at
`
` https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`
`
` 4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`
`
` 5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`
` 6 http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm
`
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`
`
`Reference ID: 4494169Reference ID: 4497378
`
`

`

`NDA 213051
`
`
`
`Page 7
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`
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`If you have any questions, call Peter Franks, Regulatory Project Manager, at
`
`
`
`
`(240) 402-4197.
`
`
`
`Sincerely,
`
`
`
`
`{See appended electronic signature page}
`
`
`Lisa B. Yanoff, M.D.
`
`Director (Acting)
`
`Division of Metabolism and Endocrinology Products
`
`
`Office of Drug Evaluation II
`
`Center for Drug Evaluation and Research
`
`
`
`
`
`ENCLOSURES:
`
`• Content of Labeling
`
`
`o Prescribing Information
`
`
`o Medication Guide
`
`
`• Carton and Container Labeling
`
`
`
`
`
`
`
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 4494169Reference ID: 4497378
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`LISA B YANOFF
`09/20/2019 07:33:44 AM
`
`
`
`Reference ID: 4494169Reference ID: 4497378
`
`(
`
`
`
`